Abstract
Recent studies directed to the design of compounds targeting the bc1 protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc1 inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol-1, are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.
| Original language | English |
|---|---|
| Pages (from-to) | 765-780 |
| Number of pages | 16 |
| Journal | Pure and Applied Chemistry |
| Volume | 89 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 27 Jun 2017 |
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Keywords
- Antimalarial activity
- ICPOC-23
- Quinoline 4-ethers
- Quinoline-type P. falciparum bc1 complex inhibitors
- Quinolone-hydroxyquinoline tautomerism
- Structural studies
- Synthesis of quinolones
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On the ordeal of quinolone preparation via cyclisation of aryl-enamines; Synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate. / Horta, Pedro; Henriques, Marta S.C.; Brás, Elisa M.; Murtinheira, Fernanda; Nogueira, Fátima; O'Neill, Paul M.; Paixaõ, José A.; Fausto, Rui; Cristiano, Maria L.S.
In: Pure and Applied Chemistry, Vol. 89, No. 6, 27.06.2017, p. 765-780.Research output: Contribution to journal › Article
TY - JOUR
T1 - On the ordeal of quinolone preparation via cyclisation of aryl-enamines; Synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate
AU - Horta, Pedro
AU - Henriques, Marta S.C.
AU - Brás, Elisa M.
AU - Murtinheira, Fernanda
AU - Nogueira, Fátima
AU - O'Neill, Paul M.
AU - Paixaõ, José A.
AU - Fausto, Rui
AU - Cristiano, Maria L.S.
PY - 2017/6/27
Y1 - 2017/6/27
N2 - Recent studies directed to the design of compounds targeting the bc1 protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc1 inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol-1, are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.
AB - Recent studies directed to the design of compounds targeting the bc1 protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc1 inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol-1, are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.
KW - Antimalarial activity
KW - ICPOC-23
KW - Quinoline 4-ethers
KW - Quinoline-type P. falciparum bc1 complex inhibitors
KW - Quinolone-hydroxyquinoline tautomerism
KW - Structural studies
KW - Synthesis of quinolones
UR - http://www.scopus.com/inward/record.url?scp=85020515500&partnerID=8YFLogxK
U2 - 10.1515/pac-2016-1119
DO - 10.1515/pac-2016-1119
M3 - Article
VL - 89
SP - 765
EP - 780
JO - Pure and Applied Chemistry
JF - Pure and Applied Chemistry
SN - 0033-4545
IS - 6
ER -